An immune response in human body is induced by a cascade of various processes which may be described as follows. First, an antigen is internalized through, e.g., phagocytosis, by antigen-presenting cells and degraded by cellular lysozyme, and the remainder forms a complex with a major histocompatibility complex(MHC) class II molecule. The resulting complex, after migrating to the outer surfacts of the antigen-presenting cell, is recognized by an antigen receptor of a helper T cell, triggering an antigen-specific humoral immune response. On the other hand, when an antigen, e.g., a viral antigen, is produced within a cell, it is degraded in the cell and the remainder forms a complex with a MHC class I molecule. The resulting complex moves to the outer surface of the virus-producing cell and an antigen-specific cellular immune response is initiated by the recognition of the complex by an antigen receptor of a cytotoxic T cell.
Subsequently, the T and antigen-presenting cells enter the initial stage of activation wherein new molecules, called accessory molecules, are expressed on their surfaces. The accessory molecules on the T cell bind to the corresponding ligand on the antigen-presenting cell and this binding accelerates the activation of the T and antigen-presenting cells, thereby promoting various immune responses. Representative accessory molecules include B7-1, B7-2, CD28, CTLA4, CD40, CD40 ligand, 4-1BB and 4-1BB ligand molecules(Goodwin et al., Eur. J. Immunol., 23, 2631(1993)).
The above-mentioned binding of accessory molecule, is indispensable for the activation of immune cells and, hence, the induction of an immune response. Accordingly, blocking of such binding may be decisive in suppressing immune responses. Further, immune responses may also be suppressed by depleting only the activated T cells which express the accessory molecules.
4-1BB, one of the accessory molecules mentioned above, was originally described as a protein expressed by activated murine T cells(Kwon, B. S., et al., Proc. Natl. Acad. Sci. U.S.A., 84, 2896-2900(1987); and Kwon, B. S. and Weissman, S. M., Proc. Natl. Acad. Sci. U.S.A., 86, 1963-1967(1989)) and subsequently demonstrated to encode a member of the tumor necrosis factor(TNF) receptor family of integral membrane proteins(Mallett, S. and Barclay, A. N., Immunol. Today, 12, 220-222(1991)). This receptor family is characterized by the presence of cysteine-rich motifs in the extracellular domains. Other members of this family include NGFR, CD40, OX-40, CD27, TNFR-I, TNFR-II, Fas and CD30(Smith, C. A., et al., Cell, 76, 959-962(1994); and Beutler, B. and VanHuffel, C., Science, 264, 667-668(1994)). 4-1BB is a 55 kDa homodimer and is expressed on a variety of murine T cell lines, thymocytes and mature T cells upon activation with concanavalin A(Con A), phytohemagglutinin(PHA) and ionomycin, or anti-CD3i(Kwon, B. S., et al., Cell. Immunol., 121, 414-422(1989); and Pollok, K. E., et al., J. Immunol., 150, 771-781(1993)). 4-1BB was found to be specifically coimmunoprecipitated with p56.sup.lck and to upregulate its own expression in Con A-stimulated thymocytes(Kim, Y. J., et al., J. Immunol., 151, 1255-1262(1993)). These results suggest that 4-1BB plays a role in intracellular signalling.
Crosslinking of 4-1BB on the surface of mouse T cell with a monoclonal antibody(MAb) resulted in a several fold enhancement of T cell proliferation when activated sub-optimally with anti-CD3i(Pollok et al., supra). The ligand for 4-1BB(4-1BBL) is found on activated macrophages and mature B cells(Goodwin, R. G., et al., Eur. J. Immunol., 23, 2631-2641(1993); Pollok, K. E., et al., Eur. J. Immunol., 24, 367-374(1994); and Alderson, M. R., et al., Eur. J. Immunol., 24, 2219-2227(1994)). 4-1BBL shows homology to TNF, LT-A, LT-B, CD40L and CD27L, which form a merging family of molecules that bind to TNF receptor family members (Goodwin, et al., supra; and Alderson et al., supra). A recent study has shown that a 4-1BB-alkaline phosphatase fusion protein blocks T cell activation in the presence or absence of B7 molecules, providing an evidence for the importance of 4-1BB and 4-1BBL interaction in costimulation of T lymphocyte activation(DeBenedette, M. A., et al. J. Exp. Med., 181, 985-992(1995)). The gene encoding human 4-1BB(h4-1BB) was recently isolated from a cDNA library of activated human peripheral T cells(Alderson, et al., supra) and the deduced amino acid sequence was shown to have 60% identity to murine 4-1BB with high conservation in the cytoplasmic domain.
On the other hand, success of an organ transplantation depends on how effectively the immunological rejection response of the organ recipient is suppressed against the transplanted organ. If the transplanted organ is not recognized by the recipient's immune system, it will function normally without the rejection problem. However, in most cases, the transplanted organ is recognized as a foreign antigen by the recipient's immune system and accordingly, immunosuppressive agents are normally used to prevent the rejection response. Exemplary immunosuppressive agents include cyclosporin, anti-lymphocyte globulin(ALG), anti-thymocyte globulin(ATG) and OKT3. However, these immunosuppressive agents tend to act not only on the activated immune cells but also on normal cells, causing serious adverse effects.
One of the most important functions of the immune system is to recognize self-antigens and discriminate them from foreign-antigens. Under normal physiological conditions, the immune system responds not to self antigens(the so-called "immunological tolerance") but only to foreign antigens. However, breakdown of the immunological tolerance may occur to produce an autoimmune response wherein the immune system recognizes self-antigens as foreign-antigens, thereby destroying self-antigens, and ultimately native cells, tissues and organs("autoimmune disease").
More than 30 diseases are known to be caused directly or indirectly by such autoimmune responses, and exemplary autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, glomerular nephritis, malignant aplastic anemia, thyroid diseases and testitis.
It is not clear at this time, exactly how such autoimmune diseases manifest themselves, and, accordingly, only limited, and after ineffective methods to treat autoimmune diseases are currently available, e. g., administration of an antiinflammatory agent to suppress inflammation caused by the autoimmune response, treatment with methotrexate which is cytotoxic to actively proliferating cells, radiotherapy or thoracic duct drainage to suppress excessive immune responses, and administration of immunosuppressive antilymphocyte serum(ASL) such as antilymphocyte globulin(ALG) and anti-thymocyte globulin(ATG). These treatments may show some short-term effectiveness, but they eventually damage normal immune calls in a long run.
Therefore, there has continued to exist a need to develop a safe immunosuppressive agent which acts selectively on activated immune cells without damaging normal immune cells.